Liver Disease

August 31, 2015

Vital Therapies has issued results of
a phase III study of VTI-208 for alcohol-induced
liver decompensation (AILD). The
randomized, controlled, open-label trial
failed to meet the primary endpoint of overall
survival through at least 91 days assessed
using the Kaplan Meier statistical method.
Of 203 total subjects enrolled in VTI-208, 96
were randomized to the treated group and
107 were randomized to the control group.
A hazard ratio of 1.027 (slightly favoring the
control group) with a log rank p=0.90 (not
statistically significant, N.S.) indicated that
there was no difference between treated
and control subjects in the primary endpoint.
The secondary endpoints of proportion
of survivors at study days 28 and 91
also showed no difference between the
groups (Pearson’s Chi-squared p=0.45 [N.S.]
and 0.74 [N.S.], respectively). The company
will be analyzing the data from the VTI-208
clinical trial during the next several weeks,
including data from the pre-specified subset
analyses. The company will stop the VTI-210
and VTI-212 clinical trials, and also plans to
meet with the FDA as soon as possible to
discuss restructuring its clinical development
program, including a potential new
trial to confirm the information suggested
by the subset analyses. The company is encouraged
that a large pre-specified subset of
120 subjects with a MELD score of less than
28 had a hazard ratio of 0.575 and a log-rank
p=0.077 (N.S.) in favor of the ELAD group,
suggesting future clinical studies should
focus on that cohort with MELD scores less
than 28. Separately, a pre-specified subset of
101 subjects under age 46.9 years (the study
median age) had a hazard ratio of 0.634
with a log-rank p=0.167 (N.S.) in favor of
the ELAD treated subjects, suggesting that
future study designs may incorporate stratification
by age. Those effects do appear to
be additive and a subset of 59 subjects with
MELD less than 28 and age less than 46.9
years had a hazard ratio of 0.375 in favor of
the ELAD group (p=0.085 [N.S.]).

April 13, 2015

GENFIT reported results of a phase IIb
trial of GFT505 for nonalcoholic steatohepatitis
(NASH). The 52-week trial enrolled 274
subjects (double-blind, placebo-controlled;
three arms: placebo, 80mg, 120mg) with
centrally-read, liver biopsy proven NASH.
Treatment with GFT505 provided a significant
beneficial effect on the primary endpoint
(GFT505 120mg v. placebo, p=0.016, RR=2.03)
in the global randomized population (n=274,
full analysis set), in which patients without an
end-of-treatment biopsy were considered as
non-responders. The primary endpoint also
was achieved in the evaluable population
of patients who underwent both baseline
and end-of-study liver biopsies (n=237, ITT;
p=0.027 v. placebo; RR=1.94). In the evaluable
patient population, GFT505 120mg also had a
beneficial effect of a decrease of NAS-score =2
(p=0.04 v. placebo). The data provide the basis
for upcoming phase III trials.

April 6, 2015

Conatus Pharmaceuticals issued results
of a phase II study of emricasan for nonalcoholic
fatty liver disease (NAFLD), including the
subset of NAFLD patients with nonalcoholic
steatohepatitis (NASH). The double-blind,
placebo-controlled trial enrolled 38 patients.
The trial met its primary endpoint, showing
a statistically significant (p<0.05) reduction
in alanine amino transferase (ALT) in patients
treated for 28 days with emricasan at 25mg
twice per day dosing compared to patients in
the placebo control group. Reductions from
baseline in ALT at day 28 of approximately
39% in the emricasan treatment arm and
approximately 14% in the placebo arm were
similar to results observed in previous trials.
Elevated baseline levels of three key serum
biomarkers—caspase-cleaved cytokeratin 18
(cCK18), full length cytokeratin 18 and caspase
3/7—also showed statistically significant
reductions from baseline in emricasan-treated
patients at day 28. A reduction from baseline
in cCK18 at Day 28 of approximately 30% in
the emricasan treatment arm and an increase
from baseline of approximately 4% in the
placebo arm were similar to results observed
in previous trials. Emricasan was safe and well
tolerated in the NAFLD/NASH trial, with no
dose-limiting toxicities and no drug-related
serious adverse events.

August 30, 2010

Immuron issued positive results from a phase I/II trial evaluating two formulations of their hyper-immune bovine colostrum powder, Imm122-I and Imm124-E, for the treatment of the liver disease non-alcoholic steatohepatitis (NASH). The open label trial enrolled 20 subjects with NASH at the Hadassah Medical Center in Jerusalem, Israel. The subjects were treated for 30 days: one group received two oral capsules, each equivalent to 100 mg Imm122-I three times a day and the other group received two oral tablets a day, each equivalent to 200 mg Imm124-E BCP. The trial demonstrated an improvement in liver function, as measured by a reduction in serum liver enzyme levels. An improvement was also seen in insulin resistance, based on fasting blood glucose levels, oral glucose tolerance test and HbA1c levels. Decreased lipid levels were seen in 70% of the subjects and 70% also showed an increase in regulatory T-cells. Both of the formulations were very well tolerated and there were no adverse events.

May 17, 2010

Raptor Pharmaceuticals issued positive results from a phase IIa trial of delayed-release cysteamine bitartrate for the treatment of non-alcoholic steatohepatitis (NASH), a progressive liver disease. This open label study enrolled 11 adolescents who were managing the disease through diet and exercise. All subjects had baseline levels of the liver enzymes alanine transaminase (ALT) and aspartate aminotransferase (AST) that were at least twice normal levels The subjects received twice-daily, escalating oral doses of up to 1,000 mg of delayed-release cysteamine bitartrate for six months. A marked decline in ALT levels was observed during the treatment period, with 7 of 11 subjects achieving a greater than 50% reduction and 6 of 11 reduced to within normal range. AST levels also saw significant improvements, with an average 41% reduction by the end of the treatment phase. The reduction in liver enzymes was largely sustained during a six month post-treatment monitoring phase. Other liver function markers also showed positive trends. Levels of cytokeratin 18, a potential marker of disease activity, decreased by an average of 45% and the levels of adiponectin, the reduction of which is related to disease pathogenesis and progression, was increased by an average of 35%. Treatment was generally well tolerated.

April 19, 2010

Intercept Pharmaceuticals issued positive results from a phase II trial of INT-747 (obeticholic acid) for primary biliary cirrhosis (PBC). This double blind, placebo controlled, dose response study enrolled 165 subjects with alkaline phosphatase (AP) values greater than or equal to 1.5 times the upper limit of normal and who had an inadequate response to ursodeoxycholic acid (UDCA) treatment. The subjects were randomized to one of three doses of INT-747 (10 mg, 25 mg or 50 mg) or placebo, both added to UDCA therapy, taken once daily for 12 weeks. The primary endpoint was reduction in AP levels at the end of the treatment period. All three doses of INT-747 significantly lowered AP by 21-24.7% with absolute values decreasing by 66-77 U/L compared to a 2.6% (5 U/L) reduction in the placebo group (p<0.0001 for all three doses). Two other liver enzymes, gamma glutamyl transferase (GGT) and alanine aminotransferase (ALT), were also reduced following treatment with INT-747. GGT was reduced by 48-63% in the three treatment groups compared to a 7% increase in the placebo group (p<0.0001 for all three doses) and ALT was reduced by 21-35% in the treatment groups with no change for placebo (p<0.005 for all three doses). The treatment was generally well tolerated.

May 21, 2007

NicOx and Axcan announced negative results from a phase IIa trial of NCX 1000 for the treatment of portal hypertension. This double-blind, dose-escalating trial enrolled 11 subjects who were randomized to receive either placebo or escalating doses of NCX 1000 (500mg, 1000mg and 2000mg as the first three doses during the first two days). This was followed by 2000mg (or the maximum tolerated dose) three times a day for the following 14 days. The primary endpoint was portal pressure on day 16 compared to baseline. Secondary endpoints included the same comparison after consumption of a controlled meal as well as response rate, increase of liver blood flow, safety, tolerability and pharmacokinetics. Results revealed a positive safety and tolerability profile. However, treatment with NCX 1000 did not provide the efficacy required to continue this trial or move into future trials. Based on the results NicOx and Axcan have agreed to terminate the development of NCX 1000.

May 22, 2006

Intercept Pharmaceuticals has announced positive results of a phase Ia trial of their investigational farnesoid X receptor agonist INT-747 for the treatment of liver tissue damage (fibrosis and obstructed bile flow) in patients with chronic liver diseases including hepatitis C viral infection, non-alcoholic steatohepatitis related to obesity, and primary biliary cirrhosis. Trial data indicated a positive preliminary tolerability profile, with no serious adverse events reported across the dosing range. This open-label, study enrolled healthy volunteers, who received single escalating doses of the drug. Based on these results, the company announced plans to initiate a phase Ib multiple-dose trial of the drug in June 2006.

December 8, 2003

Jerini AG reported positive results from a phase IIa trial investigating Icatibant (JE049), a B2 antagonist for the treatment of refractory ascites from liver cirrhosis. Results showed that the study met all primary endpoints of improved sodium and potassium excretion, urine flow, and body weight. No severe drug related adverse events during treatment were reported. The randomized crossover, placebo-controlled study enrolled subjects with decompensation (Child Pugh score 5-8). The subjects were challenged with water /sodium load and their capacity to deal with the increased sodium load was assessed. Further analysis of other parameters is ongoing.